Pulmonary arterial hypertension from a translational perspective: Bridging pathophysiology and treatment

초록

Pulmonary arterial hypertension (PAH) is a rare, progressive disorder defined by elevated pulmonary arterial pressure and vascular resistance, ultimately leading to right ventricular failure and premature death. Once considered a disease of pure vasoconstriction, PAH is now recognized as a complex vasculopathy involving endothelial dysfunction, inflammation, metabolic dysregulation, and genetic susceptibility. The pulmonary vasculature is dynamically narrowed by vasoconstriction, structurally obstructed by smooth muscle and endothelial proliferation, and pathologically stiffened by fibrosis and extracellular matrix deposition. Multiple cell types including endothelial cells, smooth muscle cells, fibroblasts, and immune cells contribute to this remodeling process. At the molecular level, hyperproliferative, apoptosis-resistant phenotypes emerge through mitochondrial dysfunction, oxidative stress, and endothelial-to-mesenchymal transition, which together drive a Warburg-like metabolic shift favoring glycolysis over oxidative phosphorylation. Chronic immune activation, characterized by cytokine release, T-cell and macrophage infiltration, and disrupted immune regulation, further amplifies vascular injury. Genetic studies have identified mutations in BMPR2, TBX4, SOX17, and other regulators of the bone morphogenic protein (BMP)/transforming growth factor-beta (TGF-beta) pathway as key contributors to heritable and idiopathic forms of PAH, highlighting impaired endothelial repair and aberrant signaling as central mechanisms. Recent translational breakthroughs have yielded novel therapeutic strategies beyond traditional vasodilators. Agents targeting the BMP/TGF-beta axis (e.g., sotatercept), growth factor signaling (seralutinib), inflammatory pathways (tocilizumab, rituximab), and metabolic remodeling (pyruvate dehydrogenase kinases [PDK] and fatty acid oxidation [FAO] modulators) are redefining treatment paradigms. Concurrently, large-scale multi-omics initiatives such as PVDOMICS and PHOENIKS enable deep phenotyping, which unravels molecular endotypes and informs precision medicine approaches. This review summarizes the pathophysiology of PAH and the ongoing clinical trials in the PAH field.

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